The overall objective of the proposal is to develop a radioligand for quantitative positron emission tomography (PET) imaging of the cerebral cannabinoid receptor (CB1) in human subjects. There is an urgent need for PET imaging of the CB1 to study the role of the cannabinoid system in schizophrenia, depression, obesity, drug dependence and many other disorders. Currently, only one radioligand is available for this purpose and its properties for imaging are poor. R21: Recently [11C]JHU75528, the first radioligand with reasonable properties for quantitative PET imaging of the CB1 receptor in animals, was developed by our group. Because of the lack of available data on PET imaging of the CB1 receptor and little cross-species information, it is not clear if [11C]JHU75528 will be satisfactory for use in humans. In the course of our Preliminary Studies, we synthesized three novel analogs of JHU75528 with in vitro properties (binding affinity and lipophilicity) superior to JHU75528. In the R21 phase these CB1 ligands will be radiolabeled with PET isotopes and tested for their PET imaging properties in baboon. The baboon PET imaging properties of three novel radioligands and the previously studied [11C]JHU75528 will be compared. Based on this comparison, the two radioligands with the best brain uptake, greatest values of binding potential (BP>1.3-1.5) in the baboon brain regions with high density of CB1 receptors and good other imaging properties will be selected for the R33 phase. R33: In the R33 phase of the project both candidate radioligands will be quantified for pharmacokinetics, distribution density, binding potential, and occupancy of the CB1 receptor in the baboon brain. Radiation dosimetry and toxicology experiments in rodents for both candidate radioligands will be conducted simultaneously with the baboon PET scans and will allow filing a physician-sponsored Exploratory IND (eIND) for these two radioligands. After the eIND approval by the FDA, the human radiotracer selection PET imaging studies with two radioligands will be performed to select the one radioligand with the highest binding potential (BP>1) and uptake in the human brain. Human radiation dosimetry will be obtained for the best radioligand. The radiation dosimetry data in humans will assure the radiation safety of the radioligand in two or more PET scans per human subject and allow carrying out human test/re-test PET scans and dose dependent occupancy of Rimonabant, a selective CB1 antagonist and an emerging anti-obesity drug. It is anticipated that clinically effective doses of Rimonabant will yield occupancy in excess of 30%. This will demonstrate in vivo saturability of the best developed here radioligand in humans and also illustrate its use as an imaging agent for the CB1 and as a biomarker in the future development of therapeutic CB1 drugs. Development of radioligands for positron emission tomography (PET) imaging of the cannabinoid receptors type 1 (CB1) is of great importance for studying the role of the cannabinoid system in neuropsychiatric disorders, obesity, drug dependence and a variety of other disorders as well as for developing cannabinergic medications to treat these conditions.